MicroRNAs Tune Protein Synthesis
Researchers at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, have generated new findings on how microRNAs (miRNA) regulate protein expression. Two teams lead by Matthias Selbach (Proteomics) and Nikolaus Rajewsky (Systems Biology) have shown that a single miRNA can directly regulate synthesis of hundreds of different proteins. In this way, miRNAs can program the way human cells act, they report in the latest issue of the journal Nature (doi:10.1038/nature07228).
All body cells contain the same genes, may they be muscle-, brain-, blood-, or liver cells. Therefore, all have the same blue prints for the production of proteins. However, different cells produce different proteins at different times - a prerequisite for the body to develop normally and stay healthy. For this to happen, genes must be regulated differently in different cell types - that is, turned on and off at the right time. Only a few years ago, researchers discovered that miRNAs play an important role in gene regulation and, thus, help determine which proteins are produced by which cells.
Proteins are the building and operating materials of life and are required for the structure, function, and regulation of the body's cells, tissues, and organs. Diseases can result if protein production goes awry. Worldwide, scientists are seeking to develop methods to detect which miRNAs are active in tissue samples and which proteins are regulated by them. To date, researchers have identified a few hundred human miRNAs but it is not clear which proteins they regulate. A further complication is that miRNAs are known to regulate synthesis of proteins, which is difficult to measure.
Using a novel experimental approach carried out by PhD students Björn Schwanhäusser and Nadine Thierfelder, the MDC researchers for the first time were able to quantify protein synthesis for thousands of different human proteins. Together with extensive computational analyses, they could further identify and quantify the direct impact of specific miRNAs on target protein synthesis.
Changing the fate of a cell
The MDC researchers could demonstrate that the regulation of protein synthesis typically is mild, with a number of interesting exceptions. "MicroRNAs screw many switches, but most of them only slightly", Matthias Selbach explains. "Thus the system is robust and flexible. A single miRNA can have profound impact on the fate of a cell. MiRNAs active in cancer cells, for example, are different from those active in normal cells."
Using a trick, the MDC researchers were for the first time able to measure changes in protein production after artificially changing the activity of specific miRNAs. They labeled amino acids (the building blocks of proteins) with a stable, non-radioactive isotope and put it together with miRNA in cell culture. This allowed them to distinguish labeled proteins in a mass spectrometer. They could show that only newly produced proteins were heavier.
A single miRNA can tune the protein levels of thousands of genes
The MDC researchers also compared the impact on protein production when artificially boosting or repressing the activity of an individual miRNA. They found that this impact is largely inverse for thousands of different proteins. Thus, 'it is as if a single miRNA can alter a large fraction of the entire protein production program of a human cell in a reversible fashion', comments Nikolaus Rajewsky.
The findings of the two Berlin research teams in collaboration with Raya Khanin from Glasgow University (UK) are anticipated to have a big impact in the future, as miRNAs are considered to be promising diagnostic and therapeutic candidates for the treatment of human diseases.